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Cancer Immunology Research
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Research Articles

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Si-Qi Liu, Alyssa Grantham, Casey Landry, Brian Granda, Rajiv Chopra, Srinivas Chakravarthy, Sabine Deutsch, Markus Vogel, Katie Russo, Katherine Seiss, William R. Tschantz, Tomas Rejtar, David A. Ruddy, Tiancen Hu, Kimberly Aardalen, Joel P. Wagner, Glenn Dranoff and Joseph A. D'Alessio
Si-Qi Liu
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Alyssa Grantham
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Casey Landry
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Brian Granda
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Rajiv Chopra
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Srinivas Chakravarthy
2BioCAT-18ID, Advanced Photon Source, Argonne National Laboratory, Argonne, Illinois.
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Sabine Deutsch
3Novartis Institutes for BioMedical Research, Basel, Switzerland.
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Markus Vogel
3Novartis Institutes for BioMedical Research, Basel, Switzerland.
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Katie Russo
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Katherine Seiss
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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William R. Tschantz
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Tomas Rejtar
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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David A. Ruddy
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Tiancen Hu
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Kimberly Aardalen
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Joel P. Wagner
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Glenn Dranoff
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Joseph A. D'Alessio
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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  • For correspondence: tony.dalessio@novartis.com
DOI: 10.1158/2326-6066.CIR-20-0080 Published January 2021
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Abstract

CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. IFNγ functioned by stimulating the expression of T-cell killing–related molecules in a cell type–specific manner. By assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Proper fucosylation of CD123 was required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T-cell–engaging CD3-bispecific antibody therapies.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:34–49

  • Received January 30, 2020.
  • Revision received June 26, 2020.
  • Accepted October 22, 2020.
  • Published first November 11, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (1)
January 2021
Volume 9, Issue 1
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A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy
Si-Qi Liu, Alyssa Grantham, Casey Landry, Brian Granda, Rajiv Chopra, Srinivas Chakravarthy, Sabine Deutsch, Markus Vogel, Katie Russo, Katherine Seiss, William R. Tschantz, Tomas Rejtar, David A. Ruddy, Tiancen Hu, Kimberly Aardalen, Joel P. Wagner, Glenn Dranoff and Joseph A. D'Alessio
Cancer Immunol Res January 1 2021 (9) (1) 34-49; DOI: 10.1158/2326-6066.CIR-20-0080

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A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy
Si-Qi Liu, Alyssa Grantham, Casey Landry, Brian Granda, Rajiv Chopra, Srinivas Chakravarthy, Sabine Deutsch, Markus Vogel, Katie Russo, Katherine Seiss, William R. Tschantz, Tomas Rejtar, David A. Ruddy, Tiancen Hu, Kimberly Aardalen, Joel P. Wagner, Glenn Dranoff and Joseph A. D'Alessio
Cancer Immunol Res January 1 2021 (9) (1) 34-49; DOI: 10.1158/2326-6066.CIR-20-0080
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